The primary goal of the research proposed in this application is to identify and characterize common genes, pathways, and networks that are involved in tumor promotion by diverse promoting stimuli. The carcinogenic process following exposure to chemical carcinogens occurs via a multi-step process involving initiation, promotion, and progression. Previous work from our laboratory using a genetic approach has provided evidence that there are common pathway(s) controlling susceptibility to tumor promotion by diverse tumor promoting stimuli including chemicals and wounding. Studies of the susceptibility to skin tumor promotion by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) have revealed that it is a multigenic trait, and we have mapped loci that modify TPA promotion susceptibility to several chromosomal regions. Using omics" approaches, we have recently identified genes that map to some of these regions that may play a role in this susceptibility (i.e., Gsta4 on chr 9, and S100A8 and S100A9 on chr 3). Additional preliminary data suggest that changes in expression of Gsta4, a gene mapping to one region, may be a common event in tumor promotion by several classes of compounds. These data suggest that an approach to uncover genetically conserved pathways could lead to discovery of common mechanisms underlying an important process (i.e., tumor promotion) in carcinogenesis. In this proposal, we will use a genetical genomics strategy to test the hypothesis that diverse classes of compounds promote the development of skin tumors through common pathways. Genes associated with these pathways will be characterized to confirm their role in the mechanism of skin tumor promotion. The specific aims of this proposal are 1) determine the strain distribution patterns (SDP) among BxD recombinant inbred (Rl) strains for susceptibility to TPA, okadaic acid (OA), and chrysarobin (Chry) skin tumor promotion, 2) examine global mRNA and protein expression profiles in epidermis of BxD Rl strains to identify common gene pathways and networks associated with tumor promotion, and 3) examine the role of Gsta4 and other candidate genes/pathways in the process of tumor promotion. The research proposed in this application will make it possible to identify new targets for cancer prevention and will likely make it possible to identify individuals with a high risk for tumor development.